| Title : ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex - Bailey_2020_Nat.Commun_11_4046 |
| Author(s) : Bailey PSJ , Ortmann BM , Martinelli AW , Houghton JW , Costa ASH , Burr SP , Antrobus R , Frezza C , Nathan JA |
| Ref : Nat Commun , 11 :4046 , 2020 |
| Abstract : 2-oxoglutarate (2-OG or alpha-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc)-the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism. |
| ESTHER : Bailey_2020_Nat.Commun_11_4046 |
| PubMedSearch : Bailey_2020_Nat.Commun_11_4046 |
| PubMedID: 32792488 |
| Gene_locus related to this paper: human-ABHD11 , mouse-Abhd11 |
| Gene_locus related to this paper: human-ABHD11 , mouse-Abhd11 |
Bailey PSJ, Ortmann BM, Martinelli AW, Houghton JW, Costa ASH, Burr SP, Antrobus R, Frezza C, Nathan JA (2020)
ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex
Nat Commun
11 :4046
Bailey PSJ, Ortmann BM, Martinelli AW, Houghton JW, Costa ASH, Burr SP, Antrobus R, Frezza C, Nathan JA (2020)
Nat Commun
11 :4046